Rotigotine is a non-ergot selective dopamine receptor agonist that produces an anti-Parkinson effect by activating D3/D2/D1 dopamine receptors. Due to the first-pass effect of the liver, the oral bioavailability of rotigotine is extremely low (about 1%-5%), which renders it unsuitable for oral administration. Currently there is no cure for Parkinson's disease. Patients thus require long-term treatment or management by drugs. Therefore, it is of great clinical significance to develop a drug characterized by a concise preparation process, low cost, and long-term steady release to improve the drug accessibility.
WO 2012/068783 discloses a rotigotine microsphere preparation capable of maintaining an effective blood drug concentration for more than two weeks. Although the microsphere preparation could achieve the objective of sustained steady release, the preparation process are complicated and accompanied by high production costs.
WO 2016/014242 discloses a series of structurally-modified derivatives of rotigotine, including rotigotine and its esters with saturated long chain of up to 16 carbons, which overcome the defect of low blood drug concentration of rotigotine for oral administration. Nevertheless, such oral dosage forms cannot achieve the objective of sustained steady release for longer than two weeks. Experiments conducted by the inventors of the present invention have revealed that injecting the saturated long-chain esters of rotigotine disclosed in WO 2016014242, such as rotigotine caprylate and rotigotine palmitate, can cause the blood drug concentration to fluctuate significantly. As such, the effective blood drug concentration is maintained for only a short period of time, and the long-term steady release of the drug cannot be achieved.
The inventors of the present invention conducted intensive studies on other saturated and unsaturated long-chain esters of rotigotine, and surprisingly found that only saturated long-chain ester of rotigotine with twenty-two carbons has both long-lasting effective blood drug concentration, high bioavailability, and long-term steady release, whereas saturated or unsaturated long-chain esters of rotigotine with more or fewer than twenty-two carbons do not have the aforementioned excellent effects.